The present invention relates to a novel compound exhibiting superior suppressive effects on cytokines directly or indirectly involved in inflammations, such as interleukin-8 (IL-8), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF-xcex1), GM-CSF and the like, and pharmaceutical agents comprising said compound, such as anti-inflammatory agents.
An inflammation is one of the protective responses in the living organisms which aims at removal of foreign substances, pathogenic bacteria and so on, as well as repair of damaged tissues. When inflammatory stimulation is received, the microcirculatory system responds and particularly increases vascular permeability. The vascular permeability is promoted by chemical mediators and cytokines. Sequentially, chemotaxis, migration and activation of neutrophiles are induced, foreign substances and pathogenic bacteria are phagocytosed at the sites of inflammation, and chemical mediators are released to induce inflammatory responses. Subsequent to neutrophiles, chemotaxis and recruitment of macrophages at the local sites occur, and activated macrophages, like neutrophiles, phagocytose foreign substances, pathogenic bacteria, disintegrated tissues and so on to produce various cytokines. Then, pathogenic bacteria, foreign substances and damaged tissues are removed and the tissues are re-constructed, whereby the inflammation comes to an end. The above-mentioned process occurs in normal inflammatory responses. In allergy and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, however, abnormal immune responses prolong inflammation and cause strong systemic symptoms.
Many cytokines are involved in various processes of inflammatory responses. For example, IL-1, TNF-xcex1 and IL-8 are responsible for the chemotaxis, adhesion to vascular endothelial cells, and migration into vascular walls, of leukocytes, which are seen during migration of leukocytes into the sites of inflammation, wherein IL-1, TNF-xcex1 and IL-8 activate neutrophiles to cause release of lysosomal enzymes and production of active oxygen and prostaglandin, thus inducing inflammation. When IL-1, TNF-xcex1 and IL-6 migrate into the circulatory system, they act on liver to induce production of acute phase inflammatory protein (e.g., CRP and SAA), and act on bone marrow to increase neutrophiles and platelets. In inflammations of connective tissues, such as rheumatoid arthritis (RA), IL-1 and TNF-xcex1 are said to activate fibroblasts and osteoclastic cells and induce production of prostaglandin and collagenase [Mebio, 11 (2), 18-23, (1994)].
As stated in the foregoing, IL-1 and TNF-xcex1 play a central role in various aspects of inflammatory responses.
Meanwhile, IL-8 is produced not only by peripheral blood monocytes and tissue macrophages, but also by large granular lymphocytes (LGL) known as natural killer cells, T lymphocytes and various tissues and cells such as fibroblasts, vascular endothelial cells and epidermal keratinocytes. Examples of production stimulators include mitogen lectins such as LPS, PHA, PSK (Coriolus versicolor-derived protein-bound polysaccharide, Krestin) and cytokines such as IL-1 and TNF-xcex1.
Although most of these cells barely produce IL-8 constantly, upon stimulation with the above-mentioned IL-8 production stimulators, they produce more than 100 times greater amounts of IL-8 within 24 hours as compared to the production without stimulation. For example, when human peripheral blood monocytes are stimulated with PSK, IL-8 mRNA is induced within an hour, and production amount of IL-8 mRNA reaches its peak in 3 hours, and gradually decreases with time. Along with the induction of IL-8 mRNA, IL-8 protein having neutrophile chemotaxisis ability is detected in the medium at 3 hours after the stimulation and increases with time. IL-8 mRNA is induced in the same manner in time as in the stimulation of IL-1 and TNF-xcex1. IL-8 is noticeably stable to protease produced by activated macrophage and the like.
The in vitro biological activities of IL-8 include chemotactic promotion, induction of degranulation, respiratory burst induction, lysosomal enzyme release induction, induction of adhesion to unstimulated or stimulated vascular endothelial cells, promotion of extravascular migration, reinforcement of expression of adhesion factors, leukotriene B4-HETH release induction and the like with regard to neutrophiles; chemotactic promotion with regard to T cells; suppressive effect on IgE production by IL-4 with regard to B cells; and chemotactic promotion and histamine.leukotriene release induction with regard to basophils. IL-8 also has in vivo activities of induction of migration of neutrophiles and lymphocytes, induction of neutrophilia, reinforcement of vascular permeability, and neutrophile-dependent arthrosynovial destruction [Rinsho Men-eki, 25 (8), 1013-1020 (1993)].
As mentioned earlier, IL-8 has various effects on neutrophiles. It has been gradually clarified that IL-8 also acts on T lymphocytes, basophils, monocytes, keratinocytes and melanoma cells, besides neutrophiles. The biological activities and target cells thereof are found to be diverse like other cytokines.
It has been known that IL-8 realizes, in vivo, migration of neutrophiles and lymphocytes at the sites of subcutaneous injections, and increases homing of T lymphocytes to local lymph nodes. It has been also known that an intravenous or intraperitoneal injection of IL-8 markedly increases neutrophile counts in peripheral blood, and administration in large amounts thereof causes destruction of alveoli. In addition, an injection of IL-8 into rabbit intra-articular joint space is known to lead to arthrosynovial destruction with migration of large amounts of neutrophiles. These results suggest strong inflammation induction by IL-8 in vivo.
In view of the fact that IL-8 has various actions besides chemotactic stimulation of neutrophile, that IL-8 was detected in synovial fluid in patients with gout or rheumatic arthritis, that IL-8 was detected from skin pieces of patients with dermatitis such as psoriasis, that IL-8-like chemotactic factor is produced by peripheral blood monocytes in asthma, and that IL-8 was detected in peripheral blood of patients with sepsis which is considered to be one of the causes of adult respiratory distress syndrome (ARDS), it is evident that IL-8 is involved in various diseases such as inflammation.
Therefore, a substance capable of suppressing cytokines responsible for inflammations, such as IL-1, IL-6, IL-8 and TNF-xcex1, is extremely useful as a new type of medicine for noninfectious or infectious diseases accompanied by neutrophile migration, which are represented by rheumatic diseases (e.g., rheumatoid arthritis); arthritis due to gout; systemic lupus erythematosus; dermatopathy (e.g., psoriasis, pustulosis and atopic dermatitis); respiratory diseases (e.g., bronchial asthma, bronchitis, ARDS and diffused interstitial pneumonia); inflammatory bowel diseases (e.g., ulcerative colitis and Crohn""s disease); acute or chronic hepatitis inclusive of fulminant hepatitis; acute or chronic glomerulonephritis; nephropyelitis; uveitis caused by Behcet disease and vogt-Koyanagi Harada disease; Mediterranean fever (polyserositis); ischemic diseases (e.g., myocardial infarction); and systemic circulatory failure and multi-organ failure caused by sepsis. In particular, such substance is expected to be effective as an anti-inflammatory agent based on new action mechanisms.
With such background of the art, compounds having inhibitory activity on inflammatory cytokines, such as IL-8, have been recently reported. For example, Japanese Patent Application under PCT laid-open under Kohyo No. 7-503017 discloses an imidazole derivative such as 4-(4-fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)imidazol as a cytokine inhibitor; Japanese Patent Application under PCT laid-open under Kohyo No. 7-503018 discloses pyridyl-substituted imidazole derivatives such as 1-(4-pyridyl)-2-(4-fluorophenyl)-4-phenylimidazol as cytokine inhibitors; and Japanese Patent Unexamined Publication No. 3-34959 discloses naphthalenemethaneamino derivatives having cytokine inhibitory activity. However, these publications do not suggest the compound of the present invention.
In addition, compounds having inhibitory activity on protease involved in inflammatory diseases have been reported. For example, Japanese Patent Unexamined Publication No. 4-330094 discloses t-butyl-oxycarbonyl-trimethylsilyl-Ala-Pro-NR-CH[(CH2)3N3]-B-pinandiole as a serine protease inhibitor of thrombin which induces pre-inflammatory changes of IL-1 and the like. Japanese Patent Examined Publication No. 7-53705 discloses phenylalanine derivatives such as N-(trans-4-amino-methylcyclohexylcarbonyl)-L-phenylalanine 4-acetylanilide. However, this publication relates to a compound characteristically having amino at one end of phenylalanine and 4-aminomethyl-6-membered ring carbonyl group at the other end, which relates to a protease inhibitor, and does not relate to an inflammatory cytokine production suppressor, such as the compound of the present invention.
An object of the present invention is to provide a compound usable as a novel selective anti-inflammatory agent which suppresses production and release of inflammatory cytokines such as IL-8, IL-1, TNF-xcex1, IL-6, and the like.
In addition, an object of the present invention is to provide a pharmaceutical agent comprising said compound.
The present inventors have conducted intensive studies with the aim of achieving the above-mentioned objects and completed the present invention.
Accordingly, the present invention provides the following.
(1) An amide compound of the formula (I) : 
xe2x80x83wherein
R is an optionally substituted non-aromatic heterocyclic group containing nitrogen, a hydroxy, Ra, an alkoxy substituted by Ra, an alkylthio substituted by Ra, or an alkylamino substituted by Ra,
wherein Ra is amino, guanidino, amidino, carbamoyl, ureido, thioureido, hydrazino hydrazinocarbonyl or imino, these groups being optionally substituted by a substituent selected from the group consisting of lower alkyl, halogenated lower alkyl, cycloalkyl, aralkyl, aryl and amino-protecting group;
A is an optionally substituted, linear or branched alkylene which optionally has one or more double bond(s) or triple bond(s) in the chain, or a single bond;
X is an oxygen atom, a sulfur atom, a cycloalkylene, a divalent aromatic heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OOCxe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94COSxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94CSxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94NR8COxe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94NR8SO2xe2x80x94, xe2x80x94SO2NR8xe2x80x94, xe2x80x94NR8xe2x80x94COOxe2x80x94, xe2x80x94OCCxe2x80x94NR8xe2x80x94, or xe2x80x94CR9R10xe2x80x94
wherein R8 is hydrogen atom, alkyl, cycloalkyl, aryl, aralkyl or amino-protecting group, and R9 and R10 are the same or different and each is hydrogen atom, alkyl, cycloalkyl, aryl or aralkyl;
M is an arylene, a cycloalkylene, or a divalent heterocyclic group which has one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, and which optionally forms a fused ring;
R1, R2, R3 and R4 are the same or different and each is a hydrogen atom, a hydroxy, a halogen atom, an alkoxy, a mercapto, an alkylthio, a nitro, a cyano, a carboxy, an alkoxycarbonyl, an aryloxycarbonyl, an acyl, an alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, lower alkoxy and halogen atom, an amino optionally substituted by a substituent selected from the group consisting of alkyl, aryl, aralkyl and amino-protecting group, or xe2x80x94Oxe2x80x94COxe2x80x94R11 
wherein R11 is optionally substituted alkoxy, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted alkylthio, optionally substituted arylthio, or alkyl optionally substituted by a substituent selected from the group consisting of alkoxycarbonyl, acyloxy, aryl, aryloxy, aryloxycarbonyl, aralkyloxy, aralkyloxycarbonyl, alkylthio, arylthio, acyl, lower alkoxy, carboxy, halogen atom and amino optionally substituted by lower alkyl or acyl;
R5 is a hydrogen atom, an alkyl optionally substituted by halogen atom, an optionally substituted aralkyl, or an amino-protecting group;
m is 0 or an integer of 1-6;
R6 is an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted lower alkylthio, an amino optionally substituted by a substituent selected from the group consisting of lower alkyl, aryl, aralkyl and amino-protecting group, or an optionally substituted heterocyclic group having one ore more hetero atoms selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom; and
R7 is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted aromatic heterocyclic group having one ore more hetero atoms selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, or xe2x80x94CO(Y)pR12 
wherein Y is oxygen atom, sulfur atom, xe2x80x94NR13xe2x80x94 or xe2x80x94NR13xe2x80x94SO2xe2x80x94
wherein R13 is hydrogen atom, alkyl, aralkyl, hydroxy, alkoxy, aryl or amino-protecting group,
p is 0 or 1, and R12 is hydrogen atom, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, adamantyl, cycloalkylideneamino, optionally substituted heterocyclic group having one or more hetero atom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, or alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, acyloxy, carboxy, heterocyclic group having one or more hetero atom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, and amino optionally substituted by a substituent selected from the group consisting of alkyl, aryl, aralkyl and amino-protecting group;
and a pharmaceutically acceptable acid addition salt thereof.
(2) The amide compound of (1) above, wherein, in the formula (I), at least one symbol selected from the group consisting of R, A, X, M, R1, R2, R3, R4, R5, m, R6 and R7 satisfies the following definitions, and a pharmaceutically acceptable acid addition salt thereof:
R is a non-aromatic heterocyclic group containing nitrogen, which is optionally substituted by lower alkyl or amino-protecting group, Ra1, an alkoxy substituted by Ra1, an alkylthio substituted Ra1, or an alkylamino substituted by Ra1,
wherein Ra1 is amino, guanidino, amidino, carbamoyl, ureido, thioureido, hydrazino, hydrazinocarbonyl or imino, these groups being optionally substituted by a substituent selected from the group consisting of lower alkyl, aralkyl and amino-protecting group;
A is a linear or branched alkylene which optionally has one or more double bond(s) or triple bond(s) in the chain, or a single bond;
X is an oxygen atom, a sulfur atom, a cycloalkylene, a divalent aromatic heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OOCxe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94COSxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94CSxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94, xe2x80x94NR8xe2x80x2xe2x80x94, xe2x80x94NR8xe2x80x2COxe2x80x94, xe2x80x94CONR8xe2x80x2xe2x80x94, xe2x80x94NR8xe2x80x2SO2xe2x80x94, xe2x80x94SO2NR8xe2x80x2xe2x80x94, xe2x80x94NR8xe2x80x2xe2x80x94COOxe2x80x94, xe2x80x94OOCxe2x80x94NR8xe2x80x2xe2x80x94, or xe2x80x94CR9xe2x80x2R10xe2x80x2xe2x80x94
wherein R8xe2x80x2 is hydrogen atom, lower alkyl, aralkyl or amino-protecting group, and R9xe2x80x2 and R10xe2x80x2 are the same or different and each is hydrogen atom, lower alkyl or aralkyl;
M is an arylene, a cycloalkylene or a divalent heterocyclic group which has one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, and which optionally forms a fused ring;
R1, R2, R3 and R4 are the same or different and each is a hydrogen atom, a hydroxy, a halogen atom, a lower alkoxy, a mercapto, a lower alkylthio, a nitro, a cyano, a carboxy, a lower alkoxycarbonyl, an aryloxycarbonyl, an acyl, a lower alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, lower alkoxy and halogen atom, an amino optionally substituted by a substituent selected from the group consisting of lower alkyl, aralkyl and amino-protecting group, or xe2x80x94Oxe2x80x94COxe2x80x94R11xe2x80x2
wherein R11xe2x80x2 is lower alkoxy, optionally substituted cycloalkyl, lower alkyl optionally substituted by a substituent selected from the group consisting of lower alkoxy-carbonyl, acyloxy, aralkyloxy, aralkyloxycarbonyl, acyl, lower alkoxy, carboxy and amino optionally substituted by lower alkyl, or aryl optionally substituted by a substituent selected from the group consisting of lower alkyl, carboxy and benzyloxycarbonyl;
R5 is a hydrogen atom, an alkyl optionally substituted by halogen atom, an optionally substituted aralkyl, or an amino-protecting group;
m is 0 or an integer of 1-6;
R6 is an aryl, a cycloalkyl or a heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom
wherein said aryl, cycloalkyl and heterocyclic group having one or more hetero atom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom are optionally substituted by a substituent selected from the group consisting of lower alkyl, halogen atom, hydroxy, lower alkoxy, amino, carboxy and lower alkoxycarbonyl; and
R7 is a hydrogen atom, a lower alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, lower alkoxy, mercapto, lower alkylthio, carboxy, lower alkoxycarbonyl and amino, an aromatic heterocyclic group which has one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, and which is optionally substituted by lower alkyl, or xe2x80x94CO(Yxe2x80x2)pR12xe2x80x2
wherein Yxe2x80x2 is oxygen atom, sulfur atom, xe2x80x94NR13xe2x80x2xe2x80x94 or xe2x80x94NR13xe2x80x2xe2x80x94SO2xe2x80x94
wherein R13xe2x80x2 is hydrogen atom, lower alkyl, aralkyl, hydroxy, lower alkoxy or amino-protecting group,
p is 0 or 1, and R12xe2x80x2 is hydrogen atom, aralkyl, adamantyl, cycloalkylideneamino, cycloalkyl optionally substituted by lower alkyl, alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxycarbonyl, acyloxy, carboxy, heterocyclic group having one or more hetero atom(s) selected from the group consisting of, nitrogen atom, sulfur atom and oxygen atom, and amino optionally substituted by a substituent selected from the group consisting of lower alkyl, aralkyl and amino-protecting group, aryl optionally substituted by a substituent selected from the group consisting of lower alkyl, halogen atom, amino, carboxy, hydroxy and lower alkoxy, or heterocyclic group which is optionally substituted by a substituent selected from the group consisting of lower alkyl, halogen atom, amino, carboxy, hydroxy and lower alkoxy, and which has one or more hetero atom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom.
(3) The amide compound of (1) above, wherein, in the formula (I), at least one symbol selected from the group consisting of R, A, X, M, R1, R2, R3, R4, R5, m, R6 and R7 satisfies the following definitions, and a pharmaceutically acceptable acid addition salt thereof:
R is a non-aromatic heterocyclic group containing nitrogen, which is optionally substituted by lower alkyl or amino-protecting group, Ra2, or an alkoxy substituted by Ra2,
wherein Ra2 is amino, guanidino, amidino or carbamoyl, these groups being optionally substituted by lower alkyl or amino-protecting group;
A is a linear alkylene or a single bond;
X is an oxygen atom, a sulfur atom, a divalent aromatic heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, xe2x80x94COOxe2x80x94, xe2x80x94OOCxe2x80x94, xe2x80x94NR8xe2x80x3xe2x80x94, xe2x80x94NR8xe2x80x3COxe2x80x94, xe2x80x94CONR8xe2x80x3xe2x80x94, xe2x80x94NR8xe2x80x3SO2xe2x80x94, xe2x80x94SO2NR8xe2x80x3xe2x80x94, or xe2x80x94CR9xe2x80x3R10xe2x80x3xe2x80x94
wherein R8xe2x80x3 is hydrogen atom, lower alkyl or amino-protecting group, and R9xe2x80x2 and R10xe2x80x2 are the same or different and each is hydrogen atom or lower alkyl;
M is an arylene or a divalent heterocyclic group which has one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, and which optionally forms a fused ring;
R1, R2, R3 and R4 are the same or different and each is a hydrogen atom, a hydroxy, a halogen atom, lower alkoxy, a lower alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, lower alkoxy and halogen atom, or xe2x80x94Oxe2x80x94COxe2x80x94R11xe2x80x3
wherein R11xe2x80x3 is lower alkoxy, cycloalkyl, aryl optionally substituted by lower alkyl, or lower alkyl optionally substituted by a substituent selected from the group consisting of acyloxy, aralkyloxycarbonyl and amino optionally substituted by lower alkyl;
R5 is a hydrogen atom, a lower alkyl, or an amino-protecting group;
m is 1;
R6 is an aryl or a cycloalkyl
wherein said aryl and cycloalkyl are optionally substituted by halogen atom or hydroxy; and
R7 is a hydrogen atom, a lower alkyl optionally substituted by hydroxy or lower alkoxy, an aromatic heterocyclic group which has one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, and which is optionally substituted by lower alkyl, or xe2x80x94CO(Yxe2x80x3)pR12xe2x80x3
wherein Yxe2x80x3 is oxygen atom, sulfur atom or xe2x80x94NR13xe2x80x3xe2x80x94
wherein R13xe2x80x3 is hydrogen atom, lower alkyl, hydroxy or amino-protecting group,
p is 0 or 1, and R12xe2x80x3 is hydrogen atom, aralkyl, adamantyl, cycloalkylideneamino, cycloalkyl optionally substituted by lower alkyl, aryl optionally substituted by halogen atom, alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxycarbonyl, acyloxy, carboxy, heterocyclic group having one or more hetero atom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, and amino optionally substituted by a substituent selected from the group consisting of lower alky, aralky and amino-protecting group, or heterocyclic group which is optionally substituted by lower alkyl, and which has one or more hetero atom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom.
(4) The amide compound of (1) above, wherein, in the formula (I), at least one symbol selected from the group consisting of R, A, X, M, R1, R2, R3, R4, R5, m, R6 and R7 satisfies the following definitions, and a pharmaceutically acceptable acid addition salt thereof:
R is a piperazinyl optionally substituted by lower alkyl, a piperidyl optionally substituted by lower alkyl, an amino, or a lower alkoxy substituted by amino wherein amino is optionally substituted by lower alkyl;
A is a linear alkylene;
X is an oxygen atom, a sulfur atom, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94;
M is an arylene;
R1, R2, R3 and R4 are the same or different and each is a hydrogen atom, a hydroxy, a halogen atom, or xe2x80x94Oxe2x80x94COxe2x80x94R11xe2x80x3xe2x80x2
wherein R11xe2x80x3xe2x80x2 is lower alkyl optionally substituted by a substituent selected from the group consisting of amino, acyloxy and benzyloxycarbonyl, or phenyl optionally substituted by lower alkyl;
R5 is a hydrogen atom;
m is 1;
R6 is a phenyl; and
R7 is xe2x80x94COOxe2x80x94R12xe2x80x2xe2x80x3
wherein R12xe2x80x2xe2x80x3, is hydrogen atom, aralkyl, adamantyl, cyclohexylideneamino, cyclohexyl optionally substituted by lower alkyl, piperidyl optionally substituted by lower alkyl, or alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxycarbonyl, acyloxy, piperazinyl and amino optionally substituted by lower alkyl.
(5) The amide compound of (4) above, wherein M is phenylene, and a pharmaceutically acceptable acid addition salt thereof.
(6) The amide compound of (4) above, wherein R7 is xe2x80x94COOxe2x80x94R12xe2x80x3xe2x80x3 wherein R12xe2x80x3xe2x80x3 is lower alkyl, or cyclohexyl which is optionally substituted by lower alkyl, and a pharmaceutically acceptable acid addition salt thereof.
(7) The amide compound of (4) above, wherein X is oxygen atom or xe2x80x94CH2xe2x80x94, and a pharmaceutically acceptable acid addition salt thereof.
(8) The amide compound of (4) above, wherein R6 is phenyl and m is 1, and a pharmaceutically acceptable acid addition salt thereof.
(9) The amide compound of (4) above, wherein R is amino optionally substituted by lower alkyl, piperazinyl optionally substituted by lower alkyl, or piperidyl optionally substituted by lower alkyl, and a pharmaceutically acceptable acid addition salt thereof.
(10) The amide compound of (4) above, wherein R1, R2, R3 and R4 are the same or different and each is hydrogen atom, hydroxy, halogen atom, or xe2x80x94Oxe2x80x94COxe2x80x94R11xe2x80x3xe2x80x3 wherein R11xe2x80x3xe2x80x3 is lower alkyl or phenyl, and a pharmaceutically acceptable acid addition salt thereof.
(11) A carboxylic acid compound of the formula (I-a) 
xe2x80x83wherein;
R is an optionally substituted non-aromatic heterocyclic group containing nitrogen, a hydroxy, Ra, an alkoxy substituted by Ra, an alkylthio substituted by Ra, or an alkylamino substituted by Ra,
wherein Ra is amino, guanidino, amidino, carbamoyl, ureido, thioureido, hydrazino, hydrazinocarbonyl or imino, these groups being optionally substituted by a substituent selected from the group consisting of lower alkyl, halogenated lower alkyl, cycloalkyl, aralkyl, aryl and amino-protecting group;
A is an optionally substituted, linear or branched alkylene which optionally has one or more double bond(s) or triple bond(s) in the chain, or a single bond;
X is an oxygen atom, a sulfur atom, a cycloalkylene, a divalent aromatic heterocyclic group having one ore more hetero atoms selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OOCxe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94COSxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94CSxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94NR8COxe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94NR8SO2xe2x80x94, xe2x80x94SO2NR8xe2x80x94, xe2x80x94NR8xe2x80x94COOxe2x80x94, xe2x80x94OOCxe2x80x94NR8xe2x80x94, or xe2x80x94CR9R10xe2x80x94
wherein R8 is hydrogen atom, alkyl, cycloalkyl, aryl, aralkyl or amino-protecting group, and R9 and R10 are the same or different and each is hydrogen atom, alkyl, cycloalkyl, aryl or aralkyl;
M is an arylene, a cycloalkylene or a divalent heterocyclic group which has one ore more hetero atoms selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, and which optionally forms a fused ring; and
R1, R2, R3 and R4 are the same or different and each is a hydrogen atom, a hydroxy, a halogen atom, an alkoxy, a mercapto, an alkylthio, a nitro, a cyano, a carboxy, an alkoxycarbonyl, an aryloxycarbonyl, an acyl, an alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, lower alkoxy and halogen atom, an amino optionally substituted by a substituent selected from the group consisting of alkyl, aryl, aralkyl and amino-protecting group, or xe2x80x94Oxe2x80x94COxe2x80x94R11 
wherein R11 is optionally substituted alkoxy, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted alkylthio, optionally substituted arylthio, or alkyl optionally substituted by a substituent selected from the group consisting of alkoxycartonyl, acyloxy, aryl, aryloxy, aryloxycarbonyl, aralkyloxy, aralkloxycarbonyl, alkylthio, arylthio, acyl, lower alkoxy, carboxy, halogen atom and amino optionally substituted by lower alkyl or acyl.
(12) The carboxylic acid compound of (11) above, wherein, in the formula (I-a), at least one of R, A, X, M, R1, R2, R3 and R4 satisfies the following definitions:
R is a piperazinyl optionally substituted by lower alkyl, a piperidyl optionally substituted by lower alkyl, an amino or a lower alkoxy substituted by amino wherein amino is optionally substituted by lower alkyl;
A is a linear alkylene;
X is an oxygen atom, a sulfur atom, xe2x80x94NHxe2x80x94 or CH2xe2x80x94;
M is an arylene; and
R1, R2, R3 and R4 are the same or different and each is a hydrogen atom, a hydroxy, a halogen atom, or xe2x80x94Oxe2x80x94COxe2x80x94R11xe2x80x3xe2x80x2
wherein R11xe2x80x3xe2x80x2 is a lower alkyl optionally substituted by a substituent selected from the group consisting of amino, acyloxy and benzyloxycarbonyl, or phenyl optionally substituted by lower alkyl.
(13) An amide compound of the formula (I-b) 
is an oxygen atom, a sulfur atom, a cycloalkylene, a divalent aromatic heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OOCxe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94COSxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94CSxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94NR8COxe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94NR8SO2xe2x80x94, xe2x80x94SO2NR8xe2x80x94, xe2x80x94NR8xe2x80x94COOxe2x80x94, xe2x80x94OOCxe2x80x94NR8xe2x80x94 or xe2x80x94CR9R10xe2x80x94
wherein R8 is hydrogen atom, alkyl, cycloalkyl, aryl, aralkyl or amino-protecting group, and R9 and R10 are the same or different and each is hydrogen atom, alkyl, cycloalkyl, aryl or aralkyl;
M is an arylene, cycloalkylene, or a divalent heterocyclic group which has one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, and which optionally forms a fused ring;
R1, R2, R3 and R4 are the same or different and each is a hydrogen atom, a hydroxy, a halogen atom, an alkoxy, a mercapto, an alkylthio, a nitro, a cyano, a carboxy, an alkoxycarbonyl, an aryloxycarbonyl, an acyl, an alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, lower alkoxy and halogen atom, an amino optionally substituted by a substituent selected from the group consisting of alkyl, aryl, aralkyl and amino-protecting group, or xe2x80x94Oxe2x80x94COxe2x80x94R11 
wherein R11 is optionally substituted alkoxy, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted alkylthio, optionally substituted arylthio, or alkyl optionally substituted by a substituent selected from the group consisting of alkoxyrarbonyl, acyloxy, aryl, aryloxy, aryloxycarbonyl, aralkyloxy, aralkyloxycarbonyl, alkylthio, arylthio, acyl, lower alkoxy, carboxy, halogen atom and amino optionally substituted by lower alkyl or acyl;
R5 is a hydrogen atom, an alkyl optionally substituted by halogen atom, optionally substituted aralkyl, or an amino-protecting group;
m is 0 or an integer of 1-6;
R6 is an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted lower allylthio, an amino optionally substituted by a substituent selected from the group consisting of lower alkyl, aryl, aralkyl and amino-protecting group, or an optionally substituted heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom; and
R7 is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted aromatic heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, or xe2x80x94CO(Y)pR12 
wherein Y is oxygen atom, sulfur atom, xe2x80x94NR13xe2x80x94 or xe2x80x94NR13xe2x80x94SO2xe2x80x94
wherein R13 is hydrogen atom, alkyl, aralkyl, hydroxy, alkoxy, aryl or amino-protecting group,
is 0 or 1, and R12 is hydrogen atom, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, adamantyl, cycloalkylideneamino, alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, acyloxy, carboxy, heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, and amino optionally substituted by a substituent selected from the group consisting of alkyl, aryl, aralkyl and amino-protecting group, or optionally substituted heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom.
(14) The amide compound of (13) above, wherein, in the formula (I-b), at least one symbol selected from the group consisting of X, M, R1, R2,
R3, R4, R5, m, R6 and R7 satisfies the following definitions:
X is an oxygen atom, a sulfur atom or xe2x80x94NHxe2x80x94;
M is an arylene;
R1, R2, R3 and R4 are the same or different and each is a hydrogen atom, a hydroxy, a halogen atom, or xe2x80x94Oxe2x80x94COxe2x80x94R11xe2x80x3xe2x80x2
wherein R11xe2x80x3xe2x80x2 is lower alkyl optionally substituted by a substituent selected from the group consisting of amino, acyloxy and benzyloxycarbonyl, or a phenyl optionally substituted by lower alkyl;
R5 is a hydrogen atom;
m is 1;
R6 is a phenyl; and
R7 is xe2x80x94COOxe2x80x94R12xe2x80x2xe2x80x3
wherein R12xe2x80x2xe2x80x3 is hydrogen atom, aralkyl, adamantyl, cyclohexyl-ideneamino, piperidyl optionally substituted by lower alkyl, cyclohexyl optionally substituted by lower alkyl, or alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxycarbonyl, acyloxy, piperazinyl, and amino optionally substituted by lower alkyl.
(15) A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and the amide compound of any one of (1) to (10) above or a pharmaceutically acceptable acid addition salt thereof.
(16) An inflammatory cytokine production suppressor comprising the amide compound of any one of (1) to (10) above or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.
(17) An agent for the treatment or prophylaxis of an inflammatory diseases, comprising the amide compound of any one of (1) to (10) above or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.
In the present specification, each substituent means as follows. xe2x80x9cAlkoxyxe2x80x9d is linear or branched alkoxy having 1 to 6 carbon atoms, which is exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy and neohexyloxy, with preference given to linear or branched alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
xe2x80x9cLower alkoxyxe2x80x9d is linear or branched alkoxy having 1 to 4 carbon atoms, which is exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, with preference given to methoxy and ethoxy.
xe2x80x9cAlkylthioxe2x80x9d is linear or branched alkylthio having 1 to 6 carbon atoms, which is exemplified by methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, tert-pentylthio, hexylthio, isohexylthio and neohexylthio.
xe2x80x9cLower alkylthioxe2x80x9d is linear or branched alkylthio having 1 to 4 carbon atoms, which is exemplified by methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio and tert-butylthio.
xe2x80x9cAlkylaminoxe2x80x9d is linear or branched, monoalkylamino or dialkylamino which has 1 to 6 carbon atoms, which is exemplified by methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino, tert-pentylamino, hexylamino, isohexylamino and neohexylamino, with preference given to linear alkylamino, such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, butylamino, pentylamino and hexylamino. Particularly preferred is linear alkylamino having 1 to 4 carbon atoms, which is exemplified by methylamino, dimethylamino, ethylamino, diethylamino, propylamino and butylamino.
xe2x80x9cNon-aromatic heterocyclic group containing nitrogenxe2x80x9d is 3- to 7-membered non-aromatic heterocyclic group which has at least one nitrogen atom and optionally a sulfur atom or oxygen atom, and which is optionally fused with benzene ring. Specific examples thereof include aziridinyl, thiazetidinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, morpholinyl, morpholino, oxazinyl, thiazinyl, piperazinyl, piperidyl, piperidino, dioxazepinyl, thiazepinyl, diazepinyl, perhydrodiazepinyl, azepinyl, perhydroazepinyl, indolinyl and isoindolinyl. Preferred are aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, morpholinyl, morpholino, piperazinyl, piperidyl, piperidino and perhydroazepinyl, and particularly preferred are pyrrolidinyl, morpholino, piperazinyl, piperidyl and piperidino.
xe2x80x9cAlkylxe2x80x9d is linear or branched alkyl having 1 to 6 carbon atoms, which is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl and neohexyl.
xe2x80x9cLower alkylxe2x80x9d is linear or branched alkyl having 1 to 4 carbon atoms, which is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
xe2x80x9cHalogen atomxe2x80x9d is specifically a fluorine atom, chlorine atom, bromine atom or iodine atom.
xe2x80x9cHalogenated lower alkylxe2x80x9d is that wherein the above-mentioned lower alkyl is substituted by a halogen atom, and is exemplified by fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, difluoroethyl, dichloroethyl, pentatrifluoroethyl, trichloroethyl and fluoropropyl, with preference given to fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl and trifluoromethyl.
xe2x80x9cCycloalkylxe2x80x9d is that having 3 to 7 carbon atoms, which is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, with preference given to cycloalkyl having 5 or 6 carbon atoms, such as cyclopentyl and cyclohexyl.
xe2x80x9cAralkylxe2x80x9d is that wherein alkyl is substituted by aryl and is exemplified by benzyl, benzhydryl, trityl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl and naphthylmethyl, with preference given to benzyl and phenethyl.
xe2x80x9cAralkyloxyxe2x80x9d is that having the above-mentioned aralkyl, which is exemplified by benzyloxy, benzhydryloxy, trityloxy, phenethyloxy, 3-phenylpropyloxy, 2-phenylpropyloxy, 4-phenylbutyloxy and naphthylmethoxy, with preference given to benzyloxy and phenethyloxy.
xe2x80x9cAralkyloxycarbonylxe2x80x9d is that having the above-mentioned aralkyl, which is exemplified by benzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, phenethyloxycarbonyl, 3-phenylpropyloxycarbonyl, 2-phenylpropyloxycarbonyl, 4-phenylbutyloxycarbonyl and naphthylmethoxycarbonyl, with preference given to benzyloxycarbonyl and phenethyloxycarbonyl.
xe2x80x9cArylxe2x80x9d is phenyl, naphthyl, anthryl, phenanthryl or biphenyl, with preference given to phenyl and naphthyl.
xe2x80x9cAryloxyxe2x80x9d is that having the above-mentioned aryl, which is exemplified by phenoxy and naphthyloxy.
xe2x80x9cAryloxycarbonylxe2x80x9d is that having the above-mentioned aryl, which is exemplified by phenoxycarbonyl and naphthyloxycarbonyl.
xe2x80x9cArylthioxe2x80x9d is that having the above-mentioned aryl, which is exemplified by phenylthio and naphthylthio.
xe2x80x9cAmino-protecting groupxe2x80x9d is a protecting group conventionally used, which is subject to no particular limitation as long as it protects amino from various reactions. Specific examples include acyl such as formyl, acetyl, propionyl, butyryl, oxalyl, succinyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2-iodoacetyl, 2,2-dichloroacetyl, 2,2,2-trichloroacetyl, 2,2,2-trifluoroacetyl, phenylacetyl, phenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl, naphthylcarbonyl, adamantylcarbonyl and phthaloyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, cyclo-hexyloxycarbonyl, 2-chloroethoxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, benzhydryloxycarbonyl, bis-(4-methoxyphenyl)methoxycarbonyl, phenacyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-triphenylsilylethoxycarbonyl and fluorenyl-9-methoxycarbonyl; alkenyloxycarbonyl such as vinyloxycarbonyl, 2-propenyloxycarbonyl, 2-chloro-2-propenyloxycarbonyl, 3-methoxycarbonyl-2-propenyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl, 2-butenyloxycarbonyl and cinnamyloxycarbonyl; aralkyloxycarbonyl such as benzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl and phenethyloxycarbonyl; lower alkylsilyl such as trimethyl-silyl and tert-butyldimethylsilyl; alkylenebis(dialkylsilyl) such as ethylenebis(dimethylsilyl), propylenebis(dimethylsilyl) and ethylene-bis(diethylsilyl); alkylthiocarbonyl such as methylthiocarbonyl, ethylthiocarbonyl, butylthiocarbonyl and tert-butylthiocarbonyl; aralkylthiocarbonyl such as benzylthiocarbonyl; phosphoryl such as dicyclohexylphosphoryl, diphenylphosphoryl, dibenzylphosphoryl, di-(4-nitrobenzyl)phosphoryl and phenoxyphenylphosphoryl; and phosphinyl such as diethylphosphinyl, diphenylphosphinyl.
xe2x80x9cLinear or branched alkylene optionally having one or more double bond(s) or triple bond(s) in the chainxe2x80x9d is linear or branched alkylene having 1 to 10 carbon atoms, which may have one ore more double bonds or triple bonds in the chain, and is exemplified by methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, dimethylmethylene, diethylmethylene, propylene, methylethylene, ethylethylene, propylethylene, isopropylethylene, methylpentaethylene, ethylhexamethylene, dimethylethylene, methyltriethylene, dimethyltrimethylene, vinylene, propenylene, butenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene, hexatrienylene, heptenylene, heptadienylene, heptatrienylene, octenylene, octadienylene, octatrienylene, octatetraenylene, propynylene, butynylene, pentynylene and methylpropynylene, with preference given to linear alkylene, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, vinylene, propenylene, butenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene, hexatrienylene, heptenylene, heptadienylene, heptatrienylene, octenylene, octadienylene, octatrienylene, octatetraenylene, propynylene, butynylene and pentynylene. Particularly preferred is linear alkylene having 1 to 8 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene and octamethylene.
xe2x80x9cDivalent aromatic heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atomxe2x80x9d is 5- or 6-membered divalent aromatic heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, which is exemplified by divalent groups of tetrazole ring, oxadiazole ring, thiadiazole ring, triazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, pyrrole ring, furan ring, thiophene ring, tetrazine ring, triazine ring, pyrazine ring, pyridazine ring, pyrimidine ring and pyridine ring. Preferred is 5-membered divalent aromatic heterocyclic group, which is exemplified by divalent groups of tetrazole ring, oxadiazole ring, thiadiazole ring, triazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, pyrrole ring, furan ring and thiophene ring. Particularly preferred are divalent groups of oxadiazole ring, thiadiazole ring and triazole ring.
xe2x80x9cCycloalkylenexe2x80x9d is that having 3 to 7 carbon atoms, namely, divalent cycloalkyl, which is specifically exemplified by cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene. Preferred is cycloalkylene having 5 or 6 carbon atoms, which is exemplified by cyclopentylene and cyclohexylene.
xe2x80x9cArylenexe2x80x9d is exemplified by phenylene, naphthylene, anthrylene, phenanthrylene and biphenylene, with preference given to phenylene, naphthylene and biphenylene.
xe2x80x9cDivalent heterocyclic group which has one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, and which optionally forms a fused ringxe2x80x9d is specifically exemplified by divalent heterocyclic groups of dioxolane ring, dithiol ring, pyrrolidine ring, morpholine ring, oxazine ring, piperazine ring, piperidine ring, pyrroline ring, imidazolidine ring, imidazoline ring, pyrazolidine ring, pyrazoline ring, thiatriazole ring, tetrazole ring, oxadiazole ring, thiadiazole ring, triazole ring, isoxazole ring, oxazole ring, thiazole ring, imidazole ring, pyrazole ring, pyrrole ring, furan ring, thiophene ring, tetrazine ring, triazine ring, pyrazine ring, pyridazine ring, pyrimidine ring, pyridine ring, furoisoxazole ring, imidazothiazole ring, thienoisothiazole ring, thienothiazole ring, imidazopyrazole ring, cyclopentapyrazole ring, pyrrolopyrrole ring, thienothiophene ring, thiadiazolopyrimidine ring, thiazolothiazine ring, thiazolopyrimidine ring, thiazolopyridine ring, oxazolopyrimidine ring; oxazolopyridine ring, benzoxazole ring, benzisothiazole ring, benzothiazole ring, imidazopyrazine ring, purine ring, pyrazolopyrimidine ring, imidazopyridine ring, benzimidazole ring, indazole ring, benzoxathiole ring, benzodioxole ring, benzodithiol ring, indolizine ring, indoline ring, isoindoline ring, furopyrimidine ring, furopyridine ring, benzofuran ring, isobenzofuran ring, thienopyrimidine ring, thienopyridine ring, benzothiophene ring, cyclopentaoxazine ring, cyclopentafuran ring, benzoxazine ring, benzothiazine ring, quinazoline ring, naphthyridine ring, quinoline ring, isoquinoline ring, benzopyran ring, pyridopyridazine ring and pyridopyrimidine ring. Preferred are divalent heterocyclic groups of piperazine ring, piperidine ring, pyridine ring, benzoxazole ring, benzisothiazole ring, benzothiazole ring and benzimidazole ring.
xe2x80x9cAlkoxycarbonylxe2x80x9d is linear or branched alkoxycarbonyl having 2 to 7 carbon atoms, which is exemplified by methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl and neohexyloxycarbonyl, with preference given to linear or branched alkoxycarbonyl having 2 to 5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl.
xe2x80x9cLower alkoxycarbonylxe2x80x9d is linear or branched alkoxycarbonyl having 2 to 5 carbon atoms, which is exemplified by methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl, with preference given to methoxycarbonyl and ethoxycarbonyl.
xe2x80x9cAcylxe2x80x9d specifically means, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, caproyl, isocaproyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, benzoyl, naphthoyl, toluoyl, hydroatropoyl, atropoyl, cinnamoyl, furoyl, glyceroyl, tropoyl, benziloyl, salicyloyl, anisoyl, vanilloyl, veratroyl, piperonyloyl, protocatechuoyl or galloyl, with preference given to formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, benzoyl and naphthoyl.
xe2x80x9cAcyloxyxe2x80x9d is that having the above-mentioned acyl, which is exemplified by formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, caproyloxy, isocaproyloxy, acryloyloxy, propioloyloxy, methacryloyloxy, crotonoyloxy, isocrotonoyloxy, benzoyloxy, naphthoyloxy, toluoyloxy, hydroatropoyloxy, atropoyloxy, cinnamoyloxy, furoyloxy, glyceroyloxy, tropoyloxy, benziloyloxy, salicyloyloxy, anisoyloxy, vanilloyloxy, veratroyloxy, piperonyloyloxy, protocatechuoyloxy and galloyloxy, with preference given to formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, benzoyloxy and naphthoyloxy.
xe2x80x9cHeterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atomxe2x80x9d at R6 is 3- to 7-membered heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, which is exemplified by aziridinyl, oxiranyl, azetyl, azetidinyl, oxetanyl, thiatriazolyl, tetrazolyl, dithiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, dioxolanyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, tetrazinyl, dithiadiazinyl, thiadiazinyl, triazinyl, morpholinyl, morpholino, oxazinyl, thiazinyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidyl, piperidino, pyridyl, pyranyl, thiopyranyl, dioxazepinyl, diazepinyl and azepinyl. Preferred is 5- or 6-membered heterocyclic group, which is exemplified by thiatriazolyl, tetrazolyl, dithiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, dioxolanyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, tetrazinyl, dithiadiazinyl, thiadiazinyl, triazinyl, morpholinyl, morpholino, oxazinyl, thiazinyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidyl, piperidino, pyridyl, pyranyl and thiopyranyl. Particularly preferred are pyrrolyl, furanyl, thienyl, piperazinyl, piperidyl, piperidino and pyridyl.
xe2x80x9cAromatic heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygenxe2x80x9d is 5- or 6-membered aromatic heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom, which is exemplified by tetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, thienyl, tetrazinyl, triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyridyl. Preferred is 5-membered aromatic heterocyclic group, which is exemplified by tetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl and thienyl. Particularly preferred are oxadiazolyl, thiadiazolyl and triazolyl.
xe2x80x9cAlkoxyalkoxyxe2x80x9d is that wherein linear or branched alkoxy having 1 to 6 carbon atoms has been substituted by linear or branched alkoxy having 1 to 6 carbon atoms, and is exemplified by methoxymethoxy, ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy, isobutoxymethoxy, sec-butoxymethoxy, tert-butoxymethoxy, pentyloxymethoxy, isopentyloxymethoxy, neopentyloxymethoxy, tert-pentyloxymethoxy, hexyloxymethoxy, isohexyloxymethoxy, neohexyloxymethoxy, tert-hexyloxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, isopropoxyethoxy, butoxyethoxy, isobutoxyethoxy, sec-butoxyethoxy, tert-butoxyethoxy, pentyloxyethoxy, isopentyloxyethoxy, neopentyloxyethoxy, tert-pentyloxyethoxy, hexyloxyethoxy, isohexyloxyethoxy, neohexyloxyethoxy, tert-hexyloxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, isopropoxypropoxy, butoxypropoxy, isobutoxypropoxy, sec-butoxypropoxy, tert-butoxypropoxy, pentyloxypropoxy, isopentyloxypropoxy, neopentyloxypropoxy, tert-pentyloxypropoxy, hexyloxypropoxy, isohexyloxypropoxy, neohexyloxypropoxy, tert-hexyloxypropoxy, methoxybutoxy, ethoxybutoxy, propoxybutoxy, isopropoxybutoxy, butoxybutoxy, isobutoxybutoxy, sec-butoxybutoxy, tert-butoxybutoxy, pentyloxybutoxy, isopentyloxybutoxy, neopentyloxybutoxy, tert-pentyloxybutoxy, hexyloxybutoxy, isohexyloxybutoxy, neohexyloxybutoxy, tert-hexyloxybutoxy, methoxypentyloxy, ethoxypentyloxy, propoxypentyloxy, isopropoxypentyloxy, butoxypentyloxy, isobutoxypentyloxy, sec-butoxypentyloxy, tert-butoxypentyloxy, pentyloxypentyloxy, isopentyloxypentyloxy, neopentyloxypentyloxy, tert-pentyloxypentyloxy, hexyloxypentyloxy, isohexyloxypentyloxy, neohexyloxypentyloxy, tert-hexyloxypentyloxy, methoxyhexyloxy, ethoxyhexyloxy, propoxyhexyloxy, isopropoxyhexyloxy, butoxyhexyloxy, isobutoxyhexyloxy, sec-butoxyhexyloxy, tert-butoxyhexyloxy, pentyloxyhexyloxy, isopentyloxyhexyloxy, neopentyloxyhexyloxy, tert-pentyloxyhexyloxy, hexyloxyhexyloxy, isohexyloxyhexyloxy, neohexyloxyhexyloxy and tert-hexyloxyhexyloxy. Preferred is that wherein linear or branched alkoxy having 1 to 4 carbon atoms has been substituted by linear or branched alkoxy having 1 to 4 carbon atoms, and is exemplified by methoxymethoxy, ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy, isobutoxymethoxy, sec-butoxymethoxy, tert-butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, isopropoxyethoxy, butoxyethoxy, isobutoxyethoxy, sec-butoxyethoxy, tert-butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, isopropoxypropoxy, butoxypropoxy, isobutoxypropoxy, sec-butoxypropoxy, tert-butoxypropoxy, methoxybutoxy, ethoxybutoxy, propoxybutoxy, isopropoxybutoxy, butoxybutoxy, isobutoxybutoxy, sec-butoxybutoxy and tert-butoxybutoxy.
xe2x80x9cLower alkoxy lower alkoxyxe2x80x9d is that wherein linear or branched alkoxy having 1 to 4 carbon atoms has been substituted by linear or branched alkoxy having 1 to 4 carbon atoms, and is exemplified by methoxymethoxy, ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy, isobutoxymethoxy, sec-butoxymethoxy, tert-butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, isopropoxyethoxy, butoxyethoxy, isobutoxyethoxy, sec-butoxyethoxy, tert-butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, isopropoxypropoxy, butoxypropoxy, isobutoxypropoxy, sec-butoxypropoxy, tert-butoxypropoxy, methoxybutoxy, ethoxybutoxy, propoxybutoxy, isopropoxybutoxy, butoxybutoxy, isobutoxybutoxy, sec-butoxybutoxy and tert-butoxybutoxy, with preference given to methoxymethoxy, ethoxymethoxy, methoxyethoxy and ethoxyethoxy.
xe2x80x9cHeterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygenxe2x80x9d at R12 means 3- to 7-membered heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen, and is exemplified by aziridinyl, oxiranyl, azetyl, azetidinyl, oxetanyl, thiatriazolyl, tetrazolyl, dithiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, dioxolanyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, tetrazinyl, dithiadiazinyl, thiadiazinyl, triazinyl, morpholinyl, morpholino, oxazinyl, thiazinyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidyl, piperidino, pyridyl, pyranyl, thiopyranyl, dioxazepinyl, diazepinyl and azepinyl. Preferred is 5- or 6-membered heterocyclic group, such as thiatriazolyl, tetrazolyl, dithiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, dioxolanyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, tetrazinyl, dithiadiazinyl, thiadiazinyl, triazinyl, morpholinyl, morpholino, oxazinyl, thiazinyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidyl, piperidino, pyridyl, pyranyl and thiopyranyl. Particularly preferred are pyrrolyl, piperazinyl, piperidyl, piperidino and pyridyl.
xe2x80x9cAlkenylxe2x80x9d is linear or branched alkenyl having 2 to 6 carbon atoms, which is exemplified by allyl, vinyl, propenyl, isopropenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-methyl-1-butenyl, crotyl, 1-methyl-3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 1-methyl-2-pentenyl, 4-pentenyl, 1-hexenyl, 3-hexenyl and 4-hexenyl.
xe2x80x9cAlkynylxe2x80x9d is linear or branched alkynyl having 2 to 6 carbon atoms, which is exemplified by propargyl, 2-butynyl, 1-methyl-2-butynyl, 2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 1-hexynyl and 5-hexynyl.
xe2x80x9cCycloalkylideneaminoxe2x80x9d specifically means cyclopropylideneamino, cyclobutylideneamino, cyclopentylideneamino, cyclohexylideneamino and cycloheptylideneamino, with preference given to cyclopentylideneamino and cyclohexylideneamino.
xe2x80x9cAlkoxyxe2x80x9d of the substituted alkoxy at R is linear or branched alkoxy having 1 to 6 carbon atoms, which is exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy and neohexyloxy, with preference given to linear alkoxy, such as methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy. Particularly preferred is linear alkoxy having 1 to 4 carbon atoms, which is exemplified by methoxy, ethoxy, propoxy and butoxy.
xe2x80x9cAlkylthioxe2x80x9d of the substituted alkylthio at R is linear or branched alkylthio having 1 to 6 carbon atoms, which is exemplified by methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, tert-pentylthio, hexylthio, isohexylthio and neohexylthio, with preference given to linear alkylthio such as methylthio, ethylthio, propylthio, butylthio, pentylthio and hexylthio. Particularly preferred is linear alkylthio having 1 to 4 carbon atoms, which is exemplified by methylthio, ethylthio, propylthio and butylthio.
xe2x80x9cOptionally substitutedxe2x80x9d of xe2x80x9coptionally substituted non-aromatic heterocyclic group containing nitrogenxe2x80x9d means that the group may be substituted by 1 to 3 substituent(s) and said substituents may be the same or different. The position of the substituent(s) is optional and is not particularly limited. Specific examples of the substituents include the above-mentioned lower alkyl, the above-mentioned halogenated lower alkyl, the above-mentioned cycloalkyl, the above-mentioned aralkyl, the above-mentioned aryl, and the above-mentioned amino-protecting group. Preferred are lower alkyl and amino-protecting group.
xe2x80x9cOptionally substitutedxe2x80x9d of xe2x80x9coptionally substituted linear or branched alkylene which may have one or more double bond(s) or triple bond(s) in the chainxe2x80x9d means that the group may be substituted by one or more substituent(s). Examples of the substituents include the above-mentioned halogen atom, hydroxy, amino which may be substituted by a substituent selected from the group consisting of the above-mentioned lower alkyl, the above-mentioned halogenated lower alkyl, the above-mentioned cycloalkyl, the above-mentioned aralkyl, the above-mentioned aryl and the above-mentioned amino protecting group, the above-mentioned lower alkoxy, the above-mentioned aralkyl and the above-mentioned cycloalkyl.
xe2x80x9cOptionally substitutedxe2x80x9d of xe2x80x9coptionally substituted alkoxyxe2x80x9d and xe2x80x9coptionally substituted alkylthioxe2x80x9d at R11 means that the group may be substituted by one or more substituent(s), and said substituents may be the same or different. The position of the substituent(s) is optional and is not particularly limited. Specific examples of the substituents include the above-mentioned halogen atom, the above-mentioned lower alkoxy, the above-mentioned alkylthio, amino which may be substituted by the above-mentioned lower alkyl or the above-mentioned acyl, carboxy, the above-mentioned alkoxycarbonyl, the above-mentioned acyl, the above-mentioned acyloxy, the above-mentioned aryl, the above-mentioned aryloxy, the above-mentioned arylthio, the above-mentioned aryloxycarbonyl, the above-mentioned aralkyloxy, and the above-mentioned aralkyloxycarbonyl. Preferred are amino, lower alkoxy, halogen atom, carboxy, alkoxycarbonyl and aralkyloxycarbonyl.
xe2x80x9cOptionally substitutedxe2x80x9d of xe2x80x9coptionally substituted arylxe2x80x9d, xe2x80x9coptionally substituted cycloalkylxe2x80x9d, xe2x80x9coptionally substituted aryloxyxe2x80x9d, xe2x80x9coptionally substituted aralkyloxyxe2x80x9d and xe2x80x9coptionally substituted arylthioxe2x80x9d at R11 means that they may have 1 to 3 substituent(s) on the ring wherein said substituents may be the same or different. The position of the substituent(s) is optional and is not particularly limited. Specific examples of the substituents include the above-mentioned lower alkyl, the above-mentioned halogen atom, the above-mentioned lower alkoxy, the above-mentioned alkylthio, amino which may be substituted by the above-mentioned lower alkyl or the above-mentioned acyl, carboxy, the above-mentioned alkoxycarbonyl, the above-mentioned acyl, the above-mentioned acyloxy, the above-mentioned aryl, the above-mentioned aryloxy, the above-mentioned arylthio, the above-mentioned aryloxycarbonyl, the above-mentioned aralkyloxy and the above-mentioned aralkyloxycarbonyl. Preferred are lower alkyl, amino, lower alkoxy, halogen atom, carboxy, alkoxycarbonyl and aralkyloxycarbonyl. Particularly preferred is lower alkyl.
xe2x80x9cOptionally substitutedxe2x80x9d of xe2x80x9coptionally substituted aralkylxe2x80x9d at R5 means that it may have 1 to 3 substituent(s) on aryl wherein said substituents may be the same or different. The position of the substituent(s) is optional and is not particularly limited. Specific examples of the substituents include the above-mentioned lower alkyl, the above-mentioned lower alkoxy, the above-mentioned acyl, amino which may be substituted by the above-mentioned lower alkyl or the above-mentioned acyl, the above-mentioned alkoxycarbonyl, the above-mentioned aryloxycarbonyl, the above-mentioned aryloxy, the above-mentioned alkylthio, the above-mentioned arylthio, the above-mentioned aryl, and the above-mentioned halogen atom. Preferred are lower alkyl, lower alkoxy and halogen atom. Particularly preferred is lower alkyl.
xe2x80x9cOptionally substitutedxe2x80x9d of xe2x80x9coptionally substituted lower alkylxe2x80x9d, xe2x80x9coptionally substituted lower alkoxyxe2x80x9d and xe2x80x9coptionally substituted lower allylthioxe2x80x9d at R6 means that the group may be substituted by one or more substituent(s) and said substituents may be the same or different. The position of the substituent(s) is optional and is not particularly limited. Specific examples of the substituents include the above-mentioned halogen atom, hydroxy, the above-mentioned alkoxy, the above-mentioned aryloxy, amino which may be substituted by the above-mentioned lower alkyl or the above-mentioned acyl, mercapto, the above-mentioned alkylthio, the above-mentioned arylthio, carboxy, the above-mentioned alkoxycarbonyl, the above-mentioned aryloxycarbonyl, carbamoyl, the above-mentioned halogenated lower alkyl, sulfamoyl, cyano, nitro, alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, alkylsulfinyl such as methylsulfinyl, ethylsulfinyl and isopropylsulfinyl, and arylsulfonyl such as phenylsulfonyl. Preferred are halogen atom, hydroxy, alkoxy, amino, carboxy and alkoxycarbonyl.
xe2x80x9cOptionally substitutedxe2x80x9d of xe2x80x9coptionally substituted arylxe2x80x9d, xe2x80x9coptionally substituted cycloalkylxe2x80x9d and xe2x80x9coptionally substituted heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atomxe2x80x9d at R6 means that the group may be substituted by one or more substituent(s) and said substituents may be the same or different. The position of the substituent(s) is optional and is not particularly limited. Specific examples of the substituents include the above-mentioned lower alkyl, the above-mentioned halogen atom, hydroxy, the above-mentioned alkoxy, the above-mentioned aryloxy, amino which may be substituted by the above-mentioned lower alkyl or the above-mentioned acyl, mercapto, the above-mentioned alkylthio, the above-mentioned arylthio, carboxy, the above-mentioned alkoxycarbonyl, the above-mentioned aryloxycarbonyl, carbamoyl, the above-mentioned halogenated lower alkyl, sulfamoyl, cyano, nitro, alkylsulfonyl such as methylsulfonyl, ethylsulfonyl and isopropylsulfonyl, alkylsulfinyl such as methylsulfinyl, ethylsulfinyl and isopropylsulfinyl, and arylsulfonyl such as phenylsulfonyl. Preferred are lower alkyl, halogen atom, hydroxy, alkoxy, amino, carboxy and alkoxycarbonyl.
xe2x80x9cOptionally substitutedxe2x80x9d of xe2x80x9coptionally substituted alkylxe2x80x9d at R7 means that the group may be substituted by one or more substituent(s) and said substituent(s) may be the same or different. The position of the substituent(s) is optional and is not particularly limited. Specific examples of the substituents include hydroxy, the above-mentioned lower alkoxy, mercapto, the above-mentioned lower alkylthio, carboxy, the above-mentioned lower alkoxycarbonyl, halogen atom, and amino which may be substituted by the above-mentioned lower alkyl or the above-mentioned acyl. Preferred are hydroxy, halogen atom and lower alkoxy.
xe2x80x9cOptionally substitutedxe2x80x9d of xe2x80x9coptionally substituted arylxe2x80x9d and xe2x80x9coptionally substituted aromatic heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atomxe2x80x9d at R7 means that they may have 1 to 3 substituent(s) on the ring wherein said substituents may be the same or different. The position of the substituent(s) is optional and is not particularly limited. Specific examples of the substituents include the above-mentioned lower alkyl, hydroxy, the above-mentioned lower alkoxy, mercapto, the above-mentioned lower alkylthio, carboxy, the above-mentioned lower alkoxycarbonyl, halogen atom, and amino which may be substituted by the above-mentioned lower alkyl or the above-mentioned acyl. Preferred are hydroxy, lower alkyl, halogen atom and lower alkoxy.
xe2x80x9cOptionally substitutedxe2x80x9d of xe2x80x9coptionally substituted alkenylxe2x80x9d and xe2x80x9coptionally substituted alkynylxe2x80x9d at R12 means that the group may be substituted by one or more substituent(s) and said substituent(s) may be the same or different. The position of the substituent(s) is optional and is not particularly limited. Specific examples of the substituents include hydroxy, the above-mentioned alkoxy, carboxy, the above-mentioned alkoxycarbonyl, the above-mentioned acyloxy, and amino which may be substituted by the above-mentioned alkyl, the above-mentioned aryl, the above-mentioned aralkyl or the above-mentioned amino-protecting group. Preferred are hydroxy, alkoxy, carboxy, alkoxycarbonyl and acyloxy.
xe2x80x9cOptionally substitutedxe2x80x9d of optionally substituted cycloalkylxe2x80x9d, xe2x80x9coptionally substituted arylxe2x80x9d and xe2x80x9coptionally substituted heterocyclic group having one or more hetero atom(s) selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atomxe2x80x9d at R12 means that they may have 1 to 3 substituent(s) on the ring wherein said substituents may be the same or different. The position of the substituent(s) is optional and is not particularly limited. Specific examples of the substituents include hydroxy, the above-mentioned lower alkoxy, mercapto, the above-mentioned lower alkylthio, carboxy, the above-mentioned lower alkoxycarbonyl, the above-mentioned lower alkyl, amino which may be substituted by the above-mentioned lower alkyl, the above-mentioned halogen atom, carbamoyl, cyano, the above-mentioned acyl, nitro, sulfamoyl, alkoxythiocarbonyl, thioalkanoyl, alkylsulfonyl such as methylsulfonyl and ethylsulfonyl, azomethine which may be substituted by the above-mentioned lower alkyl, the above-mentioned aryl or the above-mentioned aralkyl, alkoxyamino such as methoxyamino and isopropoxyamino, hydrazino which may be substituted by the above-mentioned lower alkyl, the above-mentioned aryl or the above-mentioned aralkyl, aminooxy which may be substituted by the above-mentioned lower alkyl, the above-mentioned aryl or the above-mentioned aralkyl, and alkylsulfinyl such as methylsulfinyl. Preferred are hydroxy, lower alkyl, halogen atom, lower alkoxy, amino and carboxy.
xe2x80x9cOptionally substitutedxe2x80x9d of xe2x80x9coptionally substituted aralkylxe2x80x9d at R12 means that it may have 1 to 3 substituent(s) on aryl wherein said substituents may be the same or different. The position of the substituent(s) is optional and is not particularly limited. Specific examples of the substituents include the above-mentioned lower alkyl, the above-mentioned lower alkoxy, the above-mentioned acyl, amino which may be substituted by the above-mentioned lower alkyl or the above-mentioned acyl, the above-mentioned alkoxycarbonyl, the above-mentioned aryloxycarbonyl, the above-mentioned aryloxy, the above-mentioned alkylthio, the above-mentioned arylthio, the above-mentioned aryl, and the above-mentioned halogen atom. Preferred are lower alkyl, lower alkoxy and halogen atom.
The compounds of the present invention which is shown by the formula (I) can be synthesized by, for example, the following method, to which the synthesis method of the compounds of the present invention is not limited. 
wherein
Rxe2x80x2 is R protected by hydroxy-protecting group or amino-protecting group, which is more specifically protected Ra, protected alkoxy substituted by Ra, protected allylthio substituted by Ra, protected alkylamino substituted by Ra, protected and optionally substituted non-aromatic heterocyclic group containing nitrogen, or protected hydroxy,
wherein when R is dimethylamino, N-methylpiperazinyl or N-methylpiperidyl, Rxe2x80x2 means R itself, since R does not need to be protected,
wherein Ra is amino, guanidino, amidino, carbamoyl, ureido, thioureido, hydrazino, hydrazinocarbonyl or imino, these groups being optionally substituted by a substituent selected from the group consisting of lower alkyl, halogenated lower alkyl, cycloalkyl, aralkyl, aryl and amino-protecting group; p1 R14 is carboxy-protecting group such as methyl, ethyl, tert-butyl, allyl, phenyl, benzyl, trichloroethyl, p-nitrobenzyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl and 2-trimethylsilylethyl;
W is halogen atom;
Axe2x80x2 is A without one end methylene;
Z is hydrogen atom or substituent which activates X such as triphenylphosphonium, triphenylphosphonate and arylsulfonyl; and
A, X, M, m, R, R1, R2, R3, R4, R5, R6 and R7 are as defined above.
(Step 1)
The compound (VI) can be synthesized by reacting compound (II) and compound (III) in the presence of a combined condensing agent of triphenylphosphine, trimethylphosphine, triethylphosphine, triphenyl phosphite, trimethyl phosphite, triethyl phosphite, and the like, and diisopropyl azodicarboxylate, diethyl azodicarboxylate, dicyclohexyl azodicarboxylate, and the like, in an organic solvent such as ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, benzene, toluene and dimethylformamide, or a mixed solvent thereof, under ice-cooling to under heating.
This method is particularly preferable when X is oxygen atom or sulfur atom.
The compound (VI) can be also synthesized by the following method.
(Step 2)
The compound (VI) can be synthesized by reacting compound (IV) and compound (III) in the presence of a base such as sodium hydride, potassium hydride, lithium hydride, potassium carbonate, sodium carbonate, potassium tert-butoxide, lithium diisopropylamide, methyllithium, n-butyllithium, sec-butyllithium and tert-butyllithium, in an organic solvent such as dimethylformamide, methylene chloride, tetrahydrofuran, ether, benzene and toluene, or a mixed solvent thereof, at a temperature of from xe2x88x9278xc2x0 C. to under heating.
This method is particularly preferable when X is sulfur atom or oxygen atom.
When X is xe2x80x94SOxe2x80x94 or xe2x80x94SOxe2x80x94, the corresponding sulfide obtained in the above Step 1 or Step 2 is oxidized with an oxidizing agent such as hydrogen peroxide, peracetic acid, metaperiodate, metachloroperbenzoic acid, acyl nitrate and dinitrogen tetraoxide, to synthesize compound (VI).
The compound (VI) wherein X is particularly xe2x80x94NR8xe2x80x94 or xe2x80x94CR9R10xe2x80x94 can be also synthesized by the following method.
(Step 3)
The compound (VI) can be synthesized by condensing compound (V) and compound (III) in the presence of a suitable base (e.g., lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, n-butyllithium, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride) as necessary, in water or an organic solvent such as methanol, ethanol, dimethylformamide, ether, dioxane, tetrahydrofuran, ethyl acetate, diisopropyl ether, dimethoxyethane, toluene, hexane and dimethyl sulfoxide, or a mixed solvent thereof, and subjecting the obtained compound to catalytic reduction using hydrogen gas in the presence of a metallic catalyst such as platinum black, platinum oxide, palladium black, palladium oxide, palladium hydroxide, palladium carbon and Raney nickel, or treating the compound with a reducing agent such as sodium borohydride, sodium cyanoborohydride, trimethylsilane, triethylsilane, alkali metal-ammonia, alkali metal-ethylamine, sodium amalgam and potassium amalgam.
The compound (I) can be synthesized by subjecting compound (VI) obtained in the above Step 1, 2 or 3 to the following Steps 4-6.
(Step 4)
The compound (VII) can be synthesized by reacting compound (VI) in the presence of a hydroxide or carbonate of alkali metal such as sodium, potassium and lithium, or a base such as 1,5-diazabicyclo[4.3.0]non-5-ene and 1,8-diazabicyclo[5.4.0]undec-7-ene, or an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, acetic acid and trifluoroacetic acid, in water or an organic solvent such as methanol, ethanol, dichloromethane, chloroform, tetrahydrofuran, toluene and xylene or a mixed solvent thereof, under ice-cooling to under heating, or by subjecting compound (VI) to catalytic reduction using hydrogen gas in an organic solvent such as methanol, ethanol, dimethylformamide, ether, dioxane, tetrahydrofuran and acetic acid or a mixed solvent thereof, in the presence of a metallic catalyst such as platinum black, platinum oxide, palladium black, palladium oxide, palladium carbon and Raney nickel, or by reacting compound (VI) in the presence of quaternary ammonium fluoride such as tetraethylammonium fluoride and tetra-n-butylammonium fluoride, in an organic solvent such as tetrahydrofuran, dimethylformamide and dimethyl sulfoxide or a mixed solvent thereof, under ice-cooling to under heating.
(Step 5)
The compound (Ixe2x80x2) can be synthesized by reacting compound (VII) and compound (VIII) using a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA) and carbonyldiimidazole (CDI), in the presence of an activating agent such as 1-hydroxybenzotriazole (HOBT), hydroxysuccinimide (HOSu) and N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) as necessary, in an organic solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, carbon tetrachloride and toluene or a mixed solvent thereof, under ice-cooling to under heating. When compound (VIII) is, for example, hydrochloride, this reaction can be carried out in the presence of a base such as triethylamine, N-methylmorpholine and 4-dimethylaminopyridine. When R7 is a group having hydroxy, such as xe2x80x94CONHOH and xe2x80x94CH2OH, compound (VIII) wherein said hydroxy is protected in advance is used.
(Step 6)
This step aims at eliminating the hydroxy-protecting group or amino-protecting group at Rxe2x80x2, and can be carried out according to a suitable known method. For example, when the amino-protecting group at Rxe2x80x2 is Boc (tert-butoxycarbonyl group), compound (Ixe2x80x2) is reacted in the presence of an acid such as hydrochloric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrogen chloride-dioxane, hydrogen chloride-ether and hydrogen chloride-ethyl acetate, in water or an organic solvent such as dioxane, ether, dichloromethane, tetrahydrofuran, methanol, ethanol, chloroform, benzene, toluene and ethyl acetate or a mixed solvent thereof or without solvent, to give compound (I). When the amino protecting group is, for example, benzyloxycarbonyl group, compound (I) can be synthesized by catalytic hydrogenation using hydrogen gas in water or an organic solvent such as methanol, ethanol, dimethylformamide, ether, dioxane, tetrahydrofuran and acetic acid or a mixed solvent thereof, in the presence of a metallic catalyst such as palladium carbon, platinum oxide and Raney nickel. When Rxe2x80x2 is hydroxy protected by hydroxy-protecting group, compound (I) can be synthesized by a conventional method such as catalytic hydrogenation. When R7 is protected at hydroxy, the hydroxy-protecting group is eliminated by a conventional method such as catalytic hydrogenation, and thereafter or simultaneously therewith, the above Step is carried out.
The compound (I) wherein R7 is carboxyl group can be synthesized by, for example, subjecting compound (Ixe2x80x2) wherein R7 is tert-butoxycarbonyl group or benzyloxycarbonyl group to the above-mentioned reaction. 
wherein
W1 is xe2x80x94COW3, xe2x80x94SO2W3 or xe2x80x94Oxe2x80x94COW3 wherein W3 is hydroxy or halogen atom;
W2 is hydroxy, mercapto or xe2x80x94NR8H wherein R8 is as defined above; and
A, X, M, R1, R1, R2, R3, R4 and R14 are as defined above.
The compound (VI) wherein X is xe2x80x94COOxe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94SO2NR8xe2x80x94, xe2x80x94COSxe2x80x94, xe2x80x94OOCxe2x80x94NR8xe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94 can be also synthesized by the following method.
(Step 7)
The compound (VI) can be synthesized by reacting compound (IX) and compound (X) using a condensing agent such as WSC.HCl, DCC, DPPA and CDI, in the presence of an activating agent such as HOBT, HOSu and HONB as necessary, in an organic solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, carbon tetrachloride and toluene or a mixed solvent thereof, under ice-cooling to under heating (this reaction can be carried out in the presence of a base such as triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine and N-methylpiperidine), or in the presence of a hydroxide or carbonate of alkali metal such as sodium, potassium and lithium, or a base such as triethylamine, pyridine, N-methylmorpholine, N-methylpiperidine and 4-dimethylaminopyridine, in water or an organic solvent such as dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, dimethyl sulfoxide, benzene and toluene or a mixed solvent thereof, under ice-cooling to under heating.
The compound (VI) wherein X is xe2x80x94OOCxe2x80x94, xe2x80x94NR8COxe2x80x94, xe2x80x94NR8SO2xe2x80x94 or xe2x80x94NR8xe2x80x94COOxe2x80x94 can be also synthesized by the following method.
(Step 8)
The compound (VI) can be synthesized using compound (XI) and compound (XII) according to the method of the above-mentioned Step 7.
When X is a divalent aromatic heterocyclic group having one or more hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, such as divalent oxadiazole ring, compound (VI) can be also synthesized by the following method. 
wherein A, M, R1, R1, R2, R3, R4 and R14 are as defined above.
(Step 9)
The compound (XV) can be synthesized by reacting compound (XIII) and compound (XIV) using a condensing agent such as WSC.HCl, DCC, DPPA and CDI, in the presence of an activating agent such as HOBT, HOSu and HONB as necessary, in an organic solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, carbon tetrachloride and toluene or a mixed solvent thereof, under ice-cooling to under heating. This reaction can be carried out in the presence of a base such as trimethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine and N-methylpiperidine.
(Step 10)
The compound (VIxe2x80x2) can be synthesized by heating compound (XV) in an organic solvent such as toluene, dioxane, tetrahydrofuran, benzene and xylene, or a mixed solvent thereof.
The compound (I) can be synthesized by treating compound (VI) and compound (VIxe2x80x2) obtained in the above Steps 7, 8 and 10 by the same method as in the above Steps 4-6.
When at least one of R1, R2, R3 and R4 of compound (I) is a halogen atom, compound (I) can be also synthesized by the following method. 
wherein
R1xe2x80x2, R2xe2x80x2, R3xe2x80x2 and R4xe2x80x2 are the same or different and each is hydrogen atom, hydroxy, alkoxy, mercapto, alkylthio, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, acyl, alkyl which may be substituted by a substituent selected from hydroxy, lower alkoxy and halogen atom, amino which may be substituted by a substituent selected from alkyl, aryl, aralkyl and amino-protecting group, or xe2x80x94Oxe2x80x94COxe2x80x94R11 wherein R11 is as defined above, provided that at least one of them is hydrogen atom; and
A, X, M, m, Rxe2x80x2, R1, R2, R3, R4, R5, R6 and R7 are as defined above.
(Step 11)
The compound (Ixe2x80x2) can be synthesized by reacting compound (IIxe2x80x3) in the presence of a halogenating agent such as tert-butyl hypochlorite, tert-butyl hypobromite, tert-butyl hypoiodite, sulfuryl chloride, sulfuryl bromide, thionyl chloride, thionyl bromide, fluorine, chlorine, bromine, iodine, hydrogen fluoride, silver difluoride and xenon difluoride, in an organic solvent such as dichloromethane, chloroform, acetonitrile, toluene, benzene, ether, tetrahydrofuran, dioxane, methanol, ethanol, carbon tetrachloride and ethyl acetate, or a mixed solvent thereof, or without solvent, under ice-cooling to under heating. When the protective group is removed by this step, a re-protection is applied. In the case of Boc, for example, the compound is protected with di-tert-butyl dicarbonate and the like in the presence of a suitable base such as triethylamine and pyridine.
The compound (I) can be synthesized by treating the obtained compound (Ixe2x80x2) by the same method as in the above Step 6.
The above Step 11 may be carried out after synthesizing compound (VI) corresponding to compound (Ixe2x80x3). The subsequent same treatment as in the above Steps 4-6 gives compound (I).
The compound (I) wherein at least one of R1, R2, R3 and R4 is xe2x80x94Oxe2x80x94COxe2x80x94R11 can be also synthesized by the following method. 
wherein
R1xe2x80x3, R2xe2x80x3, R3xe2x80x3 and R4xe2x80x3 are the same or different and each is hydrogen atom, hydroxy, halogen atom, alkoxy, mercapto, alkylthio, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, acyl, alkyl which may be substituted by a substituent selected from hydroxy, lower alkoxy and halogen atom, or amino which may be substituted by a substituent selected from alkyl, aryl, aralkyl and amino-protecting group, wherein at least one of them is hydroxy; and
A, X, M, m, W, Rxe2x80x2, R1, R2, R3, R4, R5, R6, R7 and R11 are as defined above.
(Step 12)
The compound (Ixe2x80x2) can be synthesized by reacting compound (Ixe2x80x2xe2x80x3) with compound (XVI) in an organic solvent such as dichloromethane, chloroform, ether, tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide, ethyl acetate and acetonitrile or a mixed solvent thereof, in the presence of a base such as pyridine, triethylamine, N-methylmorpholine, N-methylpiperidine and 4-dimethylaminopyridine.
The compound (I) can be synthesized by reacting the obtained compound (Ixe2x80x2) by the same method as in the above Step 6.
The compound of the formula (I) of the present invention can be also synthesized by the following synthetic method. 
wherein A, Axe2x80x2, X, M, m, W, Z, Rxe2x80x2, R1, R2, R3, R4, R5, R6 and R7 are as defined above.
(Step 13)
The compound (XVII) can be synthesized by subjecting compound (IIIxe2x80x2) and compound (VIII) to the same reaction as in the above Step 5.
(Step 14)
The compound (Ixe2x80x2) can be synthesized by subjecting compound (II) and compound (XVII) to the same reaction as in the above Step 1.
The compound (Ixe2x80x2) can be also synthesized by the following method.
(Step 15)
The compound (Ixe2x80x2) can be synthesized by subjecting compound (IV) and compound (XVII) to the same reaction as in the above Step 2.
The compound (Ixe2x80x2) wherein X is xe2x80x94NR8xe2x80x94 or xe2x80x94CR9R10xe2x80x94 can be also synthesized by the following method.
(Step 16)
The compound (Ixe2x80x2) can be synthesized by subjecting compound (V) and compound (XVII) to the same reaction as in the above Step 3.
The compound (I) can be synthesized by subjecting compound (Ixe2x80x2) obtained in the above Steps 14-16 to the same reaction as in the above Step 6.
The compound (Ixe2x80x2) wherein X is xe2x80x94COOxe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94SO2NR8xe2x80x94, xe2x80x94COSxe2x80x94, xe2x80x94OOCxe2x80x94NR8xe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94 can be also synthesized by the following method. 
wherein A, X, M, m, W1, W2, Rxe2x80x2, R1, R2, R3, R4, R5, R6 and R7 are as defined above.
(Step 17)
The compound (XVIII) can be synthesized by subjecting compound (Xxe2x80x2) and compound (VIII) to the same reaction as in the above Step 5.
(Step 18)
The compound (Ixe2x80x2) can be synthesized by subjecting compound (IX) and compound (XVIII) to the same reaction as in the above Step 7.
The compound (Ixe2x80x2) wherein X is xe2x80x94OOCxe2x80x94, xe2x80x94NR8COxe2x80x94, xe2x80x94NR8SO2xe2x80x94 or xe2x80x94NR8xe2x80x94COOxe2x80x94 can be also synthesized by the following method. 
wherein A, X, M, m, W1, W2, Rxe2x80x2, R1, R2, R3, R4, R5, R6 and R7 are as defined above.
(Step 19)
The compound (XIX) can be synthesized by subjecting compound (XIIxe2x80x2) and compound (VIII) to the same reaction as in the above Step 5.
(Step 20)
The compound (Ixe2x80x2) can be synthesized by subjecting compound (XI) and compound (XIX) to the same reaction as in the above Step 8.
The compound (I) can be synthesized by subjecting compound (Ixe2x80x2) obtained in the above Step 18 and Step 20 to the same reaction as in the above Step 6.
When X is xe2x80x94CR9R10xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94 or xe2x80x94CSxe2x80x94, the following step can be used for synthesis. 
wherein A, Axe2x80x2, M, X, m, W1, W2, Rxe2x80x2, R1, R2, R3, R4, R5, R6, R7 and R14 are as defined above.
(Step 21)
The compound (XXI) can be synthesized by reacting the corresponding Grignard reagent (IVxe2x80x2) obtained from compound (IV) by a conventional method, with compound (XX) in an organic solvent such as ether, tetrahydrofuran and dioxane or a mixed solvent thereof, at a temperature of from xe2x88x9278xc2x0 C. to under heating.
(Step 22)
The compound (VIxe2x80x3) can be synthesized by reacting compound (XXI) in the presence of an oxidizing agent such as chromic anhydride, pyridinium chlorochromate, manganese dioxide, sodium hypochlorite and ruthenium tetraoxide, in an organic solvent such as ether, tetrahydrofuran and dioxane or a mixed solvent thereof, under ice-cooling to under heating.
The compound (VIxe2x80x3) wherein X is xe2x80x94CSxe2x80x94 can be synthesized by reacting compound (VIxe2x80x3) obtained by the above method, in the presence of hydrogen sulfide, phosphorus pentasulfide, 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawsson""s reagent) and the like, in an organic solvent such as benzene, toluene, methanol and ethanol or a mixed solvent thereof, under ice-cooling to under heating.
(Step 23)
The compound (VIxe2x80x2xe2x80x3) can be synthesized by reacting compound (XXI) in the presence of a reducing agent such as triethylsilane, lithium alminium hydride-alminium chloride, sodium borohydride-trifluoroborane, sodium cyanoborohydride-methyl iodide and triphenylphosphonium, in an organic solvent such as ether, tetrahydrofuran and dioxane, or a mixed solvent thereof, at a temperature of from xe2x88x9278xc2x0 C. to under heating.
(Step 24)
The compound (VIxe2x80x3xe2x80x3) can be synthesized by reacting compound (XXI) in the presence of sulfuric acid, phosphoric acid, potassium hydrogensulfate, oxalic acid, p-toluenesulfonic acid, boron trifluoride-etherate, thionyl chloride-pyridine, phosphorus oxychloride-pyridine, methanesulfonyl chloride-pyridine, p-toluenesulfonyl chloride-pyridine, and the like, in an organic solvent such as ether, tetrahydrofuran and dioxane, or a mixed solvent thereof, under ice-cooling to under heating.
The compound (I) can be synthesized by treating compound (VIxe2x80x3), (VIxe2x80x2xe2x80x3) or (VIxe2x80x3xe2x80x3) obtained in the above Steps 22-24 by the same method as in the above Steps 4-6.
The compound of the formula (I) can be converted to a pharmaceutically acceptable acid addition salt by a conventional method by treating same with an inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and nitric acid) or organic acid (e.g., oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, succinic acid, citric acid, acetic acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, valeric acid, malonic acid, nicotinic acid and propionic acid).
The compound thus obtained can be separated and purified by a known method for separation and purification, such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization and chromatography.
The compound of the present invention includes one or more stereoisomers due to an asymmetric carbon, and such isomers and mixtures thereof are also encompassed in the present invention. In addition, hydrates and solvates with pharmaceutically acceptable organic solvents, as well as prodrugs of the compound of the present invention are also encompassed in the present invention.
The compound of the present invention shows superior effects of suppressing production of inflammatory cytokines in mammals such as human, rabbit, dog and cat, and is useful for the prophylaxis and treatment of noninfectious or infectious diseases accompanied by neutrophile infiltration, which are represented by rheumatic diseases (e.g., rheumatoid arthritis); arthritis due to gout; systemic lupus erythematosus; dermatopathy (e.g., psoriasis, pustulosis and atopic dermatitis); respiratory diseases (e.g., bronchial asthma, bronchitis, ARDS and diffused interstitial pneumonia); inflammatory enteric diseases (e.g., ulcerative colitis and Crohn""s disease); acute or chronic hepatitis inclusive of fulminant hepatitis; acute or chronic glomerulonephritis; nephropyelitis; uveitis caused by Behcet disease and vogt-Koyanagi Harada disease; Mediterranean fever (polyserositis); ischemic diseases (e.g., myocardial infarction); and systemic circulatory failure and multi-organ failure caused by sepsis.
The suppressive effect of the compound of the present invention on inflammatory cytokines such as IL-6 and GM-MF has been also acknowledged.
When the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation comprising same as an active ingredient, it is generally admixed with a pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrator, stabilizer, preservative, buffer, emulsifying agent, aromatic, coloring, sweetener, thickener, flavor, solubilizer and other additives such as water, vegetable oil, alcohols (e.g., ethanol and benzyl alcohol), polyethylene glycol, glycerol triacetate, gelatin, lactose and carbohydrate (e.g., starch), magnesium stearate, talc, lanolin, white petrolatum known per se to give a pharmaceutical composition in the form of tablet, pill, powder, granule, suppository, injection, eye drop, liquid, capsule, troche, aerosol, elixir, suspension, emulsion, syrup and the like, which is administered orally or parenterally.
While the dose varies depending on the kind and severity of diseases, compound to be administered, administration route, age, sex, body weight etc. of the patients, and so on, when it is orally administered to an adult patient, for example, the daily dose is generally 0.01-1,000 mg, preferably about 0.1-100 mg, and when it is intravenously administered to an adult patient, for example, the daily dose is generally 0.01-1,000 mg, preferably about 0.05-50 mg, which is administered in one or several doses.